Novel Strategy May Lead To Elimination Of AML Stem Cells

Dr. Alec (Chengcheng) Zhang Michael L. Rosenberg Scholar in Medical Research Associate Professor of Physiology and Developmental Biology Member of the Harold C. Simmons Comprehensive Cancer Center UT Southwestern Medical Interview with:
Dr. Alec (Chengcheng) Zhang
Michael L. Rosenberg Scholar in Medical Research
Associate Professor of Physiology and Developmental Biology, Member of the Harold C. Simmons Comprehensive Cancer Center
UT Southwestern Medical Center

Medical Research: What is the background for this study? What are the main findings?

Response: Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. Treatments for AML yield poor outcomes, especially for the typical senior patients. The medical need for new therapies for AML is underscored by the fact that no new therapies for AML have been approved in over 30 years. There are over 50 experimental agents in clinical trials for the treatment of AML today, although only a few agents have promising data to date. New molecular targets and therapeutic strategies are needed for AML treatment.

In 2012, we published a paper showing that we cloned the human leukocyte immunoglobulin-like receptor B2 (LILRB2) as a receptor for several angiopoietin-like proteins (Angptls) (Zheng et al 2012 Nature 485:656-660). The LILRB family receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and are classified as inhibitory receptors because ITIM motifs can recruit phosphatases SHP-1, SHP-2, or SHIP to negatively regulate immune cell activation. Surprisingly, in that work, we showed that PirB, the mouse ortholog of LILRB2, is expressed by AML stem cells (AML-SCs) and supports AML development. Although counterintuitive, this result is consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system.

In the current paper, we continued the research and report that a number of receptors containing the ITIMs are crucial for the development of AML. We mainly focus on studying the function and downstream signaling of LAIR1 as a representative ITIM-containing receptor. We found that the deletion of LAIR1 does not affect normal hematopoiesis but abolishes leukemia development in several different mouse leukemia models. We also identified a mechanism by which LAIR1 supports AML development, showing that the LAIR1/SHP-1/CAMK1/CREB pathway sustains the survival and self-renewal of AML cells. Importantly, our findings are well supported by bioinformatics analysis of AML patient databases and experimental results of human leukemia cells. Since certain ITIM-containing receptors are essential for AML cells but not critical for normal hematopoiesis, and blocking their signaling can boost immunity, these ITIM-containing receptors including LAIR1 represent ideal targets for treating AML.

Medical Research: What should clinicians and patients take away from your report?

Response: Our study suggests that, the current treatment options, including chemotherapy, may not efficiently target cancer stem cells because these inhibitory receptors enable the leukemia stem cells to survive the conventional therapies, eventually resulting in tumor relapse. The blockade of ITIM-receptor signaling may prove to be a novel effective strategy for elimination of leukemia stem cells and lead to complete remission of patients. This novel strategy may be a perfect combination of direct tumor targeting and immune therapy.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: The supportive role of LAIR1 in AML may not be an exceptional case. Our in silico analyses indicate that expression of a number of ITIM inhibitory receptors negatively correlates with AML patient survival. We speculate that these receptors may also activate the same or a similar downstream signaling pathway as LAIR1 in AML cells. Because there are numerous types of ITIM receptors, different ITIM-containing receptors may have different expression patterns in different types or subtypes of leukemia and other cancers. It will be important to investigate the mechanisms by which other ITIM-containing receptors support cancer progression. Because SHP-1 is likely a common signaling mediator of a number of ITIM-containing inhibitory receptors that may support AML development, the identification of the specific inhibitors of the phosphatase-independent SHP-1 activity for AML treatment may have significant benefits.

In addition, future investigations will be necessary to develop a better understanding of the signaling and function of these inhibitory receptors in cancer. For example, because the signaling through ITIM-containing receptors may be divergent, SHP-1 and CAMK1 may have downstream effectors other than CREB. The identification of other downstream targets of CAMK1 in leukemia cells is an important task. In addition, while we demonstrated that LAIR1/SHP-1/CAMK1/CREB is a novel signaling pathway that is essential to the activity of AML cells and that lair1 deficiency has a similar effect to the N-Myc B-ALL model, it is unclear whether different cancer cells share the same signaling. It will thus be interesting to determine the extent to which LAIR1 signaling in AML cells can be generalized to other immune inhibitory receptors and other types of cancer. Moreover, it will be important to understand whether therapeutic modalities for ITIM receptors may include antibodies against the extracellular domains of these receptors or whether inhibition of the intracellular signaling of ITIM receptors will represent a more powerful means of blocking these novel targets. Overall, blockade of ITIM-receptor signaling as a monotherapy, or in combination with conventional therapies including chemotherapy and targeted therapy may become novel strategy for AML treatment.


Xunlei Kang, Zhigang Lu, Changhao Cui, Mi Deng, Yuqi Fan, Baijun Dong, Xin Han, Fuchun Xie, Jeffrey W. Tyner, John E. Coligan, Robert H. Collins, Xiangshu Xiao, M. James You, Cheng Cheng Zhang. The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. Nature Cell Biology, 2015; 17 (5): 665 DOI: 10.1038/ncb3158

[wysija_form id=”1″] Interview with: Dr. Alec (Chengcheng) Zhang (2015).